Osteoporosis is a major metabolic bone disease that affects 44 million Americans or 55% of the people 50 years of age or older, among which 10 million individuals already have this disease and the rest 34 million more at increased high risk for osteoporosis. The disease causes a significant amount of morbidity and mortality in patients and is often diagnosed after a fracture occurs.
The endocannabinoid system plays an important role in regulating skeletal remodeling and bone mass [2, 3]. These physiological processes are implicated to play a role in the development and progression of osteoporosis. In particular, CB2-deficient mice show a remarkably accelerated age-related bone loss, supported by human genetic studies that portray polymorphisms in CNR2 gene (encoding CB2) as important genetic risk factors for osteoporosis. However, CB2-mediated bone anabolic action as well as the underlying mechanisms has not been fully explored. The present application provides compounds that can be used as probes to study the mechanisms involved in CB2-mediated regulation of osteoporotic signaling.
Multiple myeloma (MM), an incurable cancer of plasma cells is the second most common hematological malignancy in the United States. The disease disproportionately affects males over females, and is more common in the African American population than in Caucasians. The etiology of MM is unknown, and at present, there is no cure available, although modern treatment regimens have been able to slow disease progression in many patients, and have extended survival rates to about 3-5 years post-diagnosis.
MM patients present various symptoms, including hypercalcemia, anemia, renal failure, and impaired production of non-pathological immunoglobulins. Many patients also endure persistent bone pain, which typically stems from small fractures in the bones. Indeed, the hallmark pathology of MM is increased bone destruction and development of osteolytic lesions, which are mediated by high osteoclast (OCL) activity and make the patient more susceptible to bone fractures.
Previous work from the present inventors revealed that compounds belonging to the chemical genus shown below modulated cannabinoid receptor-2 activity. Preliminary biological data illustrates that this class of compounds to selectively modulate the CB2 receptor.
The cannabinoid receptor subtypes CB1 (brain) and CB2 (spleen) are important G-protein coupled receptor targets for developing new therapeutic agents. Since the discovery of the cannabinoid (CB) receptors, their endogenous ligands, and enzymes implicated to play a role in cannabinoid receptor and ligand biology there has been intensive pharmacological research into the therapeutic potential of cannabinergic ligands.
Clinical data related to the therapeutic potential of CB ligands for the treatment of nausea, glaucoma, cancer, stroke, pain, neuronal disorders, osteoporosis, multiple sclerosis, and autoimmune disorders has generated active interest in cannabinoid research. While most of the research efforts have focused on the development of ligands targeted to the CB1 receptor, biological data indicates that CB 1 ligands exert undesirable psychotropic side effects. These side effects have caused public concern. However, work to design novel CB2 ligands that do not confer psychotropic side effects associated with modulation of CB 1 activity has been limited, largely due to a lack of information about the three dimensional structures of the CB receptors and ligand binding sites.
The present inventors have used structure-activity relationship (SAR), studies to explore and define the chemical space of CB2 receptor that is involved in ligand binding interactions. Early studies used to define this chemical space relied on QSAR/NMR methodologies and in-silico docking experiments to identify a library of chemically diverse scaffolds as the core pharmacophore for CB2 receptor ligand design.